ABSTRACT: Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor (clopidogrel, prasugrel, or ticagrelor) is the standard of care after percutaneous coronary intervention (PCI) to reduce the risk of atherothrombotic events. The cytochrome P450 (CYP)2C19 enzyme is essential for metabolism of clopidogrel (a prodrug) to its pharmacologically active form. Approximately 30% of the U.S. population carries a CYP2C19 loss-of-function (LOF) allele that reduces the bioactivation and effectiveness of clopidogrel, but not prasugrel or ticagrelor, after PCI. We have demonstrated the feasibility of incorporating CYP2C19 genotyping into clinical care to guide escalation of DAPT from clopidogrel to prasugrel or ticagrelor in patients with a CYP2C19 LOF allele, and that a CYP2C19-guided escalation strategy reduced the risk for atherothrombotic events. However, the influence of key patient-specific factors on outcomes with genotype-guided DAPT (notably African ancestry, comorbidities that impact clopidogrel effectiveness, and genotypes beyond CYP2C19) has not been defined but is critical to understand in order to optimize the clinical impact of genotype-guided DAPT. Moreover, the impact on clinical outcomes of using CYP2C19 genotype to guide de-escalation from more potent agents to clopidogrel in patients without a LOF allele, which has become highly clinically relevant due to more frequent initial use of prasugrel or ticagrelor after acute coronary syndrome and PCI, has not been investigated in a diverse, real-world clinical setting. Our long-term goal is to optimize a precision medicine DAPT strategy that improves outcomes post-PCI. Our overall aim is to elucidate the key factors that influence outcomes with a CYP2C19 genotype-guided precision medicine approach to DAPT. Our hypothesis is that multiple clinical and genetic factors jointly contribute to the effectiveness and safety of CYP2C19 LOF allele- guided selection of DAPT after PCI in a real-world clinical setting. We propose to test this hypothesis by conducting a multi-center, observational study of 6,000 patients with PCI and clinical CYP2C19 genetic testing. This registry will include a diverse population of real-world patients, assess atherothrombotic and bleeding outcomes over 12 months, collect DNA samples for additional genotyping, conduct platelet reactivity testing in a subset of patients, and be used to accomplish the following specific aims: (AIM 1) define the influence of African ancestry and other patient-specific factors on clinical outcomes with CYP2C19 genotype-guided DAPT following PCI in a real-world setting; (AIM 2) evaluate the safety and effectiveness of CYP2C19 genotype- guided de-escalation of DAPT following PCI in a real-world setting; (AIM 3) elucidate the effect(s) of genetic variants beyond CYP2C19 LOF alleles on platelet reactivity and clinical outcomes with clopidogrel after PCI. This investigation will establish optimal strategies for individualized antiplatelet therapy prescribing decisions that improve outcomes and can be feasibly applied in a diverse, real-world population.